Noninvasive Monitoring of Suicide Gene Therapy by Using Multimodal Molecular Imaging

  • Bryan Holvoet
  • Cindy Leten
  • Christophe M. Deroose
  • Uwe HimmelreichEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1895)


Cells expressing suicide genes can be used as therapeutic vehicles for difficult-to-treat tumors, for example, if stem cells are used that are able to track infiltrating tumor cells. An alternative application of suicide gene expression is their use as a safety switch in regenerative medicine where the presence of a few pluripotent stem cells could potentially cause unwanted side effects like the formation of teratoma. One potential bottleneck of these applications is that information on the initiation of cell suicide is needed early on, for example, when therapeutic cells have reached infiltrating tumor cells or when teratomas are formed. Therefore, in vivo imaging methods are needed that provide information on target location, (stem) cell location, (stem) cell viability, pathology, and suicide gene expression. This requires multimodal imaging approaches that can provide this information longitudinally and in a noninvasive way. Here, we describe examples of how therapeutic cells can be modified so that they express a suicide gene and genes that can be used for in vivo visualization.

Key words

Suicide gene Magnetic resonance imaging Positron emission tomography Bioluminescence imaging Stem cells 


  1. 1.
    Leten C, Trekker J, Struys T, Dresselaers T, Gijsbers R, Vande Velde G, Lambrichts I, Van der Linden A, Verfaillie CM, Himmelreich U (2015) Assessment of bystander killing-mediated therapy of malignant brain tumors using a multimodal imaging approach. Stem Cell Res Ther 6:163CrossRefGoogle Scholar
  2. 2.
    Burns TC, Steinberg GK (2011) Stem cells and stroke: opportunities, challenges and strategies. Expert Opin Biol Ther 11:447–461CrossRefGoogle Scholar
  3. 3.
    Gürsel DB, Berry N, Boockvar JA (2012) Therapeutic stem cells encapsulated in a synthetic extracellular matrix selectively kill tumor cells, delay tumor growth, and increase survival in a mouse resection model of malignant glioma. Neurosurgery 70:N17–N19CrossRefGoogle Scholar
  4. 4.
    Kucerova L, Altanerova V, Matuskova M et al (2007) Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res 67:6304–6313CrossRefGoogle Scholar
  5. 5.
    Miletic H, Fischer Y, Litwak S et al (2007) Bystander killing of malignant glioma by bone marrow-derived tumor-infiltrating progenitor cells expressing a suicide gene. Mol Ther 15:1373–1381CrossRefGoogle Scholar
  6. 6.
    Matuskova M, Hlubinova K, Pastorakova A et al (2010) HSV-tk expressing mesenchymal stem cells exert bystander effect on human glioblastoma cells. Cancer Lett 290:58–67CrossRefGoogle Scholar
  7. 7.
    Leten C, Trekker J, Struys T, Roobrouck VD, Dresselaers T, Vande Velde G, Lambrichts I, Verfaillie CM, Himmelreich U (2016) Monitoring the bystander killing effect of human multipotent stem cells for treatment of malignant brain tumors. Stem Cells Int 2016:e4095072CrossRefGoogle Scholar
  8. 8.
    Arnhold S, Klein H, Semkova I, Addicks K, Schraermeyer U (2004) Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Invest Ophthalmol Vis Sci 45:4251–4255CrossRefGoogle Scholar
  9. 9.
    Blum B, Benvenisty N (2009) The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle 8:3822–3830CrossRefGoogle Scholar
  10. 10.
    Leten C, Roobrouck VD, Struys T et al (2014) Controlling and monitoring stem cell safety in vivo in an experimental rodent model. Stem Cells 32:2833–2844CrossRefGoogle Scholar
  11. 11.
    Duarte S, Carle G, Faneca H, de Lima MC, Pierrefite-Carle V (2012) Suicide gene therapy in cancer: where do we stand now? Cancer Lett 324:160–170CrossRefGoogle Scholar
  12. 12.
    Neyrinck K, Breuls N, Holvoet B et al (2018) The human somatostatin receptor type 2 as an imaging and suicide reporter gene for pluripotent stem cell-derived therapy of myocardial infarction. Theranostics 8: 2799–2813Google Scholar
  13. 13.
    Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B et al (2017) Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med 376:125–135CrossRefGoogle Scholar
  14. 14.
    Mori K, Iwata J, Miyazaki M, Osada H, Tange Y, Yamamoto T et al (2010) Bystander killing effect of thymidine kinase gene-transduced adult bone marrow stromal cells with ganciclovir on malignant glioma cells. Neurol Med Chir (Tokyo) 50:545–553CrossRefGoogle Scholar
  15. 15.
    Deroose CM, Reumers V, Gijsbers R, Bormans G, Debyser Z, Mortelmans L et al (2006) Noninvasive monitoring of long-term lentiviral vector-mediated gene expression in rodent brain with bioluminescence imaging. Mol Ther 14:423–431CrossRefGoogle Scholar
  16. 16.
    Waerzeggers Y, Klein M, Miletic H, Himmelreich U, Li H, Monfared P et al (2008) Multimodal imaging of neural progenitor cell fate in rodents. Mol Imaging 7:77–91CrossRefGoogle Scholar
  17. 17.
    Himmelreich U, Hoehn M (2008) Stem cell labeling for magnetic resonance imaging. Minim Invasive Ther Allied Technol 17:132–142CrossRefGoogle Scholar
  18. 18.
    Wolfs E, Holvoet B, Gijsbers R, Casteels C, Roberts SJ, Struys T et al (2014) Optimization of multimodal imaging of mesenchymal stem cells using the human sodium iodide symporter for PET and Cerenkov luminescence imaging. PLoS One 9:e94833CrossRefGoogle Scholar
  19. 19.
    Wolfs E, Holvoet B, Ordovas L, Breuls N, Helsen N, Schönberger M et al (2017) Molecular imaging of human embryonic stem cells stably expressing human PET reporter genes after zinc finger nuclease-mediated genome editing. J Nucl Med 58:1659–1665CrossRefGoogle Scholar
  20. 20.
    Himmelreich U, Dresselaers T (2009) Cell labeling and tracking for experimental models using magnetic resonance imaging. Methods 48:112–124CrossRefGoogle Scholar
  21. 21.
    Jacobs AH, Winkeler A, Hartung M, Slack M, Dittmar C, Kummer C (2003) Improved herpes simplex virus type 1 amplicon vectors for proportional coexpression of positron emission tomography marker and therapeutic genes. Hum Gene Ther 14:277–297CrossRefGoogle Scholar
  22. 22.
    Miletic H, Fischer YH, Giroglou T, Rueger MA, Winkeler A, Li H, Himmelreich U et al (2007) Normal brain cells contribute to the bystander effect in suicide gene therapy of malignant glioma. Clin Cancer Res 13:6761–6768CrossRefGoogle Scholar
  23. 23.
    Chiba K, Hockemeyer D (2015) Genome editing in human pluripotent stem cells using site-specific nucleases. Methods Mol Biol 1239:267–280CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Bryan Holvoet
    • 1
    • 2
  • Cindy Leten
    • 2
    • 3
  • Christophe M. Deroose
    • 1
    • 2
  • Uwe Himmelreich
    • 2
    • 3
    Email author
  1. 1.Nuclear Medicine and Molecular Imaging, Department of Imaging and PathologyUniversity of LeuvenLeuvenBelgium
  2. 2.Molecular Small Animal Imaging Center (MoSAIC)University of LeuvenLeuvenBelgium
  3. 3.Biomedical MRI Unit, Department of Imaging and PathologyUniversity of LeuvenLeuvenBelgium

Personalised recommendations